Transdermal drug delivery is an attractive concept as such means may offer a convenient and comfortable mode of delivery. The variable rates of absorption and metabolism encountered in oral administration are avoided, together with eliminating adverse effects such as gastro-intestinal irritation; it is a noninvasive method, and it may provide superior control of blood concentration of a particular drug over time.
However, skin is a complex structure that functions as a barrier to ingress of foreign substances into the body. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum, which presents the primary barrier to absorption of topical compositions or transdermally administered drugs, especially for oil-insoluble and ionized salt forms of drugs.
A number of different methods have been developed for transdermal drug delivery, enabling the administration of a variety of drugs. One approach includes formulations of drugs as to enable their delivery through the skin, including development of number of skin penetration enhancing agents, or “permeation enhancers”, to increase skin permeability. The formulated drugs may be applied to the skin in the forms of patches, films, or matrices of various compositions. Another approach includes non-chemical modes for facilitating transdermal delivery, e.g. the use of iontophoresis, electroporation or sonophoresis.
Transdermal Delivery Apparatus
Electrotransport or iontophoretic drug delivery devices have been disclosed as being useful for the delivery of drugs for which it is anticipated that transdermal delivery would be advantageous. U.S. Pat. Nos. 6,169,920 and 6,317,629 to Alza for example disclose iontophoretic drug delivery apparatus, and U.S. Pat. No. 5,983,130 to Alza discloses an electrotransport agent delivery method and apparatus suitable for ionizable drugs.
Electroporation is also well known in the art as a method to increase pore size by application of an electric field. Electroporation is disclosed as a means for transiently decreasing the electrical resistance of the stratum corneum and increasing the transdermal flux of small molecules by applying an electric field to increase the size of existing pores (Chizmadzhev et al., Biophysics Journal, 1998, 74 (2), 843-856).
U.S. Pat. No. 5,019,034 to Weaver et al. describes apparatus for applying high voltage, short duration electrical pulses on the skin to produce electroporation.
WO 97/07734 to Eppstein et al. discloses thermal ablation of the stratum corneum using an electrically resistive element in contact with the stratum corneum, such that a high current through the element causes a general heating of tissue in its vicinity, most particularly the stratum corneum 10-50 micron thick outermost layer of the skin.
U.S. Pat. Nos. 5,885,211, 6,022,316, 6,142,939 and 6,173,202 to Eppstein et al., which are incorporated herein by reference, describe methods for forming micropores in the stratum corneum by heating tissue-bound water above the vapor point with a heat-conducting element, so as to enhance transdermal transport of an analyte or active substance. Further enhancement techniques include the use of sonic energy, pressure, and chemical enhancers.
U.S. Pat. No. 3,964,482 to Gerstel, U.S. Pat. No. 6,050,988 to Zuck, and U.S. Pat. No. 6,083,196 to Trautman et al. describe other apparatus and methods for facilitating transdermal movement of a substance.
U.S. Pat. No. 6,148,232 to Avrahami, which is incorporated herein in its entirety by reference, describes apparatus for applying electrodes at respective points on skin of a subject and applying electrical energy of radio frequency (RF) between two or more of the electrodes to cause ablation of the stratum corneum primarily in an area intermediate the respective points, forming micro-channels. Various techniques for limiting ablation to the stratum corneum are described, including spacing of the electrodes and monitoring the electrical resistance of skin between adjacent electrodes.
The apparatus of the type disclosed in U.S. Pat. No. 6,148,232 and continuations thereto (U.S. Pat. Nos. 5,983,135; 6,597,946; and 6,611,706, and International Patent Application Nos. WO01/85234; WO 02/085451; and WO 02/092163) is referred to hereinafter by the names ViaDerm or MicroDerm.
Transdermal Patches
There are two prevalent types of transdermal patch designs, namely the reservoir type where the drug is contained within a reservoir having a basal surface that is permeable to the drug, and a matrix type, where the drug is dispersed in a polymer layer affixed to the skin. Both types of device typically include a backing layer and a release liner layer that is removed prior to use. In an effort to increase skin permeability so that the drugs can be delivered in therapeutically effective amounts, it has been proposed to pretreat the skin with various chemicals or to concurrently deliver the drug in the presence of adjuvants known as “increasers” or “permeation enhancers” to increase the rate of permeation of the active ingredient. Various materials have been suggested for this purpose, as described for example in U.S. Pat. No. 6,004,578 to Lee at al., and references therein, which are incorporated herein by reference.
However, such permeation enhancers often cause problems such as irritation, sensitization, or severe inconvenience, and therefore the number of drugs that can be safely and effectively administered through skin remains limited.
Delivery of Water-Insoluble Drugs
Many powerful drug substances are insoluble in water, limiting the effectiveness of their use as therapeutic agents. One approach to enhance the solubility of such drugs in water is to form a reversible complex between the water insoluble drug and a carrier molecule; the characteristics of the carrier molecule are such that the carrier molecule and the reversible complex are soluble in water. Among the carrier molecules are amorphous cyclodextrins described, for example, in U.S. Pat. Nos. 5,134,127; 5,376,645; 5,874,418; and 6,046,177. The use of cyclodextrin and its derivatives as solubilizing agents for water insoluble drugs for oral, intranasal, or parenteral administration is disclosed.
Steroid compounds affect a large number of important physiological functions in humans, and natural as well as synthetic steroids and their derivatives are in use for therapeutic purposes. Methods of steroid administration depend both on the steroid and on the specific disorder. Many of the beneficial steroids that are administered therapeutically to patients are insoluble in water.
The steroid testosterone is the main androgenic hormone formed in the testes. Testosterone therapy is indicated for the treatment of male hypogonadism, and is also suggested for treatment of wasting conditions associated with AIDS and cancer, for treatment of osteoporosis, and for combination hormone replacement therapy for women and male fertility control.
Transdermal delivery of androgens, alone or in combination with estrogenic agents has been disclosed, for example, in U.S. Pat. Nos. 4,867,982; 5,460,820; 5,622,944; and 6,214,374; and in International Patent Application Nos. WO 95/03764; WO 97/24148; WO 98/37871; and WO 00/76522. Many of the cited patents disclose the use of various patches for the transdermal delivery of testosterone. One limitation in the use of such patches is the requirement for scrotal application, which presents problems of inconvenience to the patients (U.S. Pat. Nos. 4,704,282; and 5,840,327). Although non-scrotal application was also suggested (for example, U.S. Pat. Nos. 5,152,997; and 6,132,760), efficient delivery through skin requires the use of permeation enhancers, which by themselves may cause severe problems of irritation and sensitization. In addition, the size of suggested patches is, for small patches, at the range of 30 cm2, while most frequently used patches are at a size range of 60 cm2. Another limitation in the use of such patches is the inability to adequately control androgen serum concentrations and hence androgen bioavailability. Transdermal delivery of androgen formulated into gels was also suggested (e.g. WO 0217927); the main limitation of administering androgen by way of a gel is the resulted undesired contamination of other subjects being in a close contact with the subject in need.
The use of amorphous cyclodextrins for pharmaceutical formulation of steroids to enable therapeutic administration has been disclosed, but nowhere in the background art is it taught or suggested that these formulations are suitable for transdermal use.
The aforementioned U.S. Pat. No. 5,874,418 demonstrates the utility of a specific cyclodextrin derivative having 7 sulfoalkyl ether substituents, (SBE)7-β-cyclodextrin, for the preparation of sustained release formulation of a pharmacologically active agent, with testosterone serving as an example.
U.S. Pat. No. 5,824,668 discloses compositions including at least one 5β steroid and an amorphous cyclodextrin formulated for parenteral administration. International Patent application WO 96/16659 discloses stabilized suspension of corticosteroids with cyclodextrins useful for therapeutic treatment of the eye, ear and nose.
Thus, there is a recognized need for, and it will be highly advantageous to have compositions and methods for an efficient transdermal delivery of water-insoluble drugs in general, and water insoluble steroids in particular, which scarcely cause irritation and are applied to small skin areas.